Congenital abnormalities of the kidney and urinary tract (CAKUT) are the leading cause of end stage renal disease among children under 5 years, with an occurrence of approximately 1 in 500 newborns. Among the several genetic mutations that have been linked to CAKUT are mutations in Notch signaling pathway genes, Jagged-1 and Notch2. Mutations in Notch pathway genes, predicted to reduce the level of Notch signaling activity, are associated with Alagille Syndrome (ALGS), one component of which is the formation of small multi-cystic, dysplastic kidneys. Recently, the Hajdu-Cheney syndrome, also involving renal cysts, is associated with mutations in Notch2. Although the Notch pathway mutations are correlated with human pediatric syndromes including smaller kidneys and renal cysts, the underlying cellular and molecular mechanisms by which Notch signaling regulates nephron formation are only beginning to be understood. The objective of this project is to improve our understanding of the cellular and molecular mechanisms regulating renal proximal tubule morphogenesis and hence to contribute to better treatment options and better management of patients suffering from CAKUT. We propose to utilize the Notch signaling pathway as a molecular handle to identify the cellular and molecular mechanisms regulating renal proximal tubule morphogenesis. We have recently identified that reducing the level of Notch signaling during kidney development in mice results in small multi-cystic, dysplastic kidneys, proving that Notch signaling plays a critical role in renal tubule morphogenesis.
In aim 1 we will use the mice with Notch signaling deficient kidneys, and three renal cell lines with Notch signaling inactivation to identify the cellular processes and genes by which Notch signaling regulates renal epithelial cell division during tubule morphogenesis. Additionally, in aim2 we will identify proteins and pathways that Notch signaling interacts with in regulating renal proximal tubule morphogenesis. This will involve testing the hypothesis that mutations in the Notch pathway genes that partially inactivate Notch signaling will modify the kidney disease in Pkd2 +/- mice. It will also involve an unbiased screen for proteins that interact with the intracellular domain of Notch2. These studies will improve our understanding of the cellular and molecular mechanisms regulating renal proximal tubule morphogenesis and in general the mechanisms by which epithelia are retained as a monolayer while they divide.
How Notch signaling regulates epithelial cell division will have a broad impact on understanding Notch signaling as a tumor suppressor in the kidney, lung, skin, head and neck. These studies have the potential to discover novel functions of Notch, novel interactions with Notch receptors and novel genes regulated by Notch signaling, all of which will aid in finding molecular therapies for improving the health of human with CAKUT, ALGS, Hajdu-Cheney syndrome, polycystic kidney disease and Notch-dependent cancers.
|White, Katherine A; Swier, Vicki J; Cain, Jacob T et al. (2018) A porcine model of neurofibromatosis type 1 that mimics the human disease. JCI Insight 3:|
|Anderson, Ruthellen H; Lensing, Cody J; Forred, Benjamin J et al. (2018) Differentiating Antiproliferative and Chemopreventive Modes of Activity for Electron-Deficient Aryl Isothiocyanates against Human MCF-7 Cells. ChemMedChem 13:1695-1710|
|Johnson, Tyler B; Mechels, Keegan; Anderson, Ruth Ellen et al. (2018) Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1. Sci Rep 8:16161|
|Brudvig, J J; Cain, J T; Sears, R M et al. (2018) MARCKS regulates neuritogenesis and interacts with a CDC42 signaling network. Sci Rep 8:13278|
|Roux, Kyle J; Kim, Dae In; Burke, Brian et al. (2018) BioID: A Screen for Protein-Protein Interactions. Curr Protoc Protein Sci 91:19.23.1-19.23.15|
|Hussain, Sajjad; Bedekovics, Tibor; Liu, Qiuying et al. (2018) UCH-L1 bypasses mTOR to promote protein biosynthesis and is required for MYC-driven lymphomagenesis in mice. Blood 132:2564-2574|
|Brudvig, J J; Cain, J T; Schmidt-Grimminger, G G et al. (2018) MARCKS Is Necessary for Netrin-DCC Signaling and Corpus Callosum Formation. Mol Neurobiol 55:8388-8402|
|Anderson, Ruthellen H; Kerkvliet, Jason G; Otta, Jaelin J et al. (2018) Generation of a CLTA reporter human induced pluripotent stem cell line, CRMi001-A-1, using the CRISPR/Cas9 system to monitor endogenous clathrin trafficking. Stem Cell Res 33:95-99|
|Lucido, Christopher T; Callejas-Valera, Juan L; Colbert, Paul L et al. (2018) ?2-Adrenergic receptor modulates mitochondrial metabolism and disease progression in recurrent/metastatic HPV(+) HNSCC. Oncogenesis 7:81|
|McKenzie, Casey W; Preston, Claudia C; Finn, Rozzy et al. (2018) Strain-specific differences in brain gene expression in a hydrocephalic mouse model with motile cilia dysfunction. Sci Rep 8:13370|
Showing the most recent 10 out of 59 publications